Central CCL2 signaling onto MCH neurons mediates metabolic and behavioral adaptation to inflammation

EMBO Rep. 2016 Dec;17(12):1738-1752. doi: 10.15252/embr.201541499. Epub 2016 Oct 12.


Sickness behavior defines the endocrine, autonomic, behavioral, and metabolic responses associated with infection. While inflammatory responses were suggested to be instrumental in the loss of appetite and body weight, the molecular underpinning remains unknown. Here, we show that systemic or central lipopolysaccharide (LPS) injection results in specific hypothalamic changes characterized by a precocious increase in the chemokine ligand 2 (CCL2) followed by an increase in pro-inflammatory cytokines and a decrease in the orexigenic neuropeptide melanin-concentrating hormone (MCH). We therefore hypothesized that CCL2 could be the central relay for the loss in body weight induced by the inflammatory signal LPS. We find that central delivery of CCL2 promotes neuroinflammation and the decrease in MCH and body weight. MCH neurons express CCL2 receptor and respond to CCL2 by decreasing both electrical activity and MCH release. Pharmacological or genetic inhibition of CCL2 signaling opposes the response to LPS at both molecular and physiologic levels. We conclude that CCL2 signaling onto MCH neurons represents a core mechanism that relays peripheral inflammation to sickness behavior.

Keywords: CCL2 chemokine; CCR2 signaling pathway; melanin‐concentrating hormone; neuroinflammation; weight loss.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chemokine CCL2 / deficiency
  • Chemokine CCL2 / genetics*
  • Chemokine CCL2 / immunology
  • Chemokine CCL2 / metabolism*
  • Cytokines / biosynthesis
  • Cytokines / genetics
  • Cytokines / immunology
  • Hypothalamic Hormones / genetics
  • Hypothalamic Hormones / immunology
  • Hypothalamic Hormones / metabolism*
  • Hypothalamus / metabolism*
  • Illness Behavior
  • Inflammation / metabolism*
  • Lipopolysaccharides / immunology
  • Melanins / genetics
  • Melanins / immunology
  • Melanins / metabolism*
  • Mice
  • Neurons / immunology
  • Neurons / metabolism*
  • Pituitary Hormones / genetics
  • Pituitary Hormones / immunology
  • Pituitary Hormones / metabolism*
  • Receptors, CCR2 / metabolism
  • Signal Transduction*
  • Weight Loss


  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Cytokines
  • Hypothalamic Hormones
  • Lipopolysaccharides
  • Melanins
  • Pituitary Hormones
  • Receptors, CCR2
  • melanin-concentrating hormone